Background:  HIV-associated sensory neuropathy (HIV-SN) is the most common form of peripheral neuropathy recognized among HIV/AIDS patients. HIV-SN includes neuropathy directly related to HIV infection per se and neuropathy associated with the use of the nucleoside analogue reverse transcriptase inhibitors (NRTI). We have previously shown that recombinant HIV-1 clones containing env sequences amplified from peripheral nerves of HIV/AIDS patients were CCR5-dependent, macrophage tropic and induced neurite retraction in sensory neurons. Herein, using an in vitro tissue culture system we have extended these studies to investigate the potential mechanisms of HIV-SN.

Methods:  Dorsal root ganglion (DRG) mixed cell cultures generated from human CD4/CCR5 transgenic rats were infected with recombinant HIV-1 clones containing env sequences amplified from peripheral nerves of HIV/AIDS patients. Neuropathogenic effects were evaluated by measuring neurite lengths and cell soma size of MAP-2⁺ DRG neurons. Host immune responses in the DRG cultures and the peripheral nerve tissue from HIV/AIDS patients were investigated using real time PCR analysis for pro-inflammatory cytokine expression.

Results:  Recombinant HIV-1 clones induced a significant reduction in the neurite length (p < 0.005) and cell soma size (p < 0.001) of MAP-2⁺ DRG neurons, depending on the virus strain. Real-time PCR analysis demonstrated enhanced IL-1β and TNF-α expression in DRG cultures infected with the recombinant HIV-1 clones. HIV-1 infection of DRG cultures also resulted in Schwann cell activation, as evidenced by enhanced GFAP expression. In addition, IL-1β and IL-6 were detected in peroneal nerves from HIV/AIDS patients. Supporting these findings, supernatants from macrophages of human CD4/CCR5 transgenic rats infected with different recombinant HIV-1 clones induced significant cell death in neuronal cells.

Conclusions:  Our results suggest that HIV-1 infection of the peripheral nervous system causes neuronal degeneration, possibly through an indirect mechanism mediated by Schwann cell activation and pro-inflammatory cytokine (e.g., TNF-α and/or IL-1β) production by peripheral nerve resident macrophages.

Keywords: HIV-associated sensory neuropathy; Axonal degeneration; Pro-inflammatory cytokines